权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Prognostic Significance of Neuronal Differentiation of Cutaneous Melanoma

皮肤黑色素瘤神经元分化的预后意义

基本信息

批准号：
7587326
负责人：
Vijayasaradhi Setaluri
金额：
$ 16.54万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587326
关键词：
American Joint Committee on Cancer Apoptosis Attention Biological Biological Markers Cell Cycle Arrest Cell Death Cell Differentiation process Cell Line Cell Proliferation Cell division Cells Chromosome Segregation Clinical Cutaneous Cutaneous Melanoma Cytokinesis Defect Dendrites Development Diagnosis Differentiation Antigens Disease Disease-Free Survival Early Diagnosis Exhibits Frequencies G2/M Arrest Gene Expression Genes Goals Growth In Vitro Investigation Lesion Malignant Neoplasms Melanoma Cell Metastatic Lesion Metastatic Melanoma Microtubule Stabilization Microtubule-Associated Protein 2 Microtubules Mitosis Mitotic Mitotic Spindle Apparatus Mitotic spindle Molecular Neoplasm Metastasis Neoplastic Melanocyte Neuronal Differentiation Neurons Outcome Pathway interactions Patients Phase Primary Neoplasm Prognostic Marker Proliferation Marker Property Proteins Radial Growth Phase Regression Analysis S-Phase Fraction Sentinel Lymph Node Series Skin Cancer Staging Staging System Stem cells Survival Analysis Testing Thick Vertical Growth Phase abstracting apoptotic protease-activating factor 1 cell type cohort interest melanoma mimicry minimally invasive molecular marker neoplastic cell nerve stem cell nestin protein novel marker overexpression precursor cell prognostic prognostic indicator relating to nervous system stem tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cutaneous melanoma is thought to progress through a series of distinct phases that include a non-invasive or minimally invasive radial growth phase and a vertical growth phase that acquires metastatic capacity. According to the widely accepted staging system, vertical thickness of primary tumor is the best predictor of the aggressiveness of melanoma. However, tumor thickness is not always a reliable parameter. Although a number of other clinical and biological parameters that influence melanoma progression have been identified, to date there are no molecular markers that can reliably predict aggressiveness of melanoma. Malignant melanoma is also known to exhibit molecular plasticity and transdifferentiate along several cellular pathways, including endothelial and neural cell types. Melanoma transdifferentiation seems to have biological and prognostic significance. We have investigated the effects of neuronal differentiation on melanoma tumor progression. We showed that the neuron-specific microtubule associated protein 2 (MAP2), a protein found primarily in the dendrites of post-mitotic, terminally differentiated neurons, is expressed abundantly in early invasive cutaneous primary melanoma lesions but present only less frequently or absent in metastatic lesions. MAP2 expression appears to be inversely correlated with tumor progression. The primary function of MAP2 is to stabilize microtubules. MAP2 alters the 'dynamic instability' of microtubules, a property critical for mitotic spindle formation and chromosome segregation. Therefore, we hypothesized that neuronal differentiation and activation of MAP2 gene expression in neoplastic melanocytes that are destined to divide rapidly, disrupts mitotic apparatus, inhibits cell proliferation and tumor progression. Retrospective immuno-histochemical and survival analysis of a small cohort showed that patients whose primary tumors were MAP2-positive had significantly longer disease-free survival than those with MAP2-negative melanoma. Investigation of the mechanisms that underlie the effects of MAP2 showed that overexpression of MAP2 in metastatic melanoma cells leads to stabilization of microtubules, G2-M arrest, growth inhibition followed by apoptosis. MAP2 expressing cells show mitotic spindle and cytokinesis defects similar to those seen in cells treated with microtubule-disrupting agents. Thus, ectopic activation of a neuronal differentiation gene in melanoma during early progression inhibits cell division and correlates with inhibition or delay of metastasis. The goal of this study is to test the hypothesis that expression of neuronal markers in cutaneous primary melanoma reduces tumor cell proliferative potential, increases the frequency of cell death and is associated with longer disease-free survival of patients. We propose to test and validate neuronal markers nestin, NEDD9 and MAP2 as a melanoma prognostics marker by investigating the association between MAP2 expression and a) markers for melanoma cell proliferation and apoptosis, and b) clinical outcome in patients diagnosed with melanoma. PUBLIC HEALTH RELEVANCE: Cutaneous melanoma is the deadliest form of skin cancer. If diagnosed early and treated appropriately before the cancer becomes aggressive, melanoma is often curable. However, there are no biological markers to reliably assess the aggressiveness of melanoma. The goal of this project is to assess the value of novel markers in predicting melanoma tumor aggressiveness.

描述(申请人提供)：皮肤黑色素瘤被认为经历了一系列不同的阶段，包括非侵入性或微侵袭性的径向生长期和获得转移能力的垂直生长期。根据被广泛接受的分期系统，原发肿瘤的垂直厚度是预测黑色素瘤侵袭性的最佳指标。然而，肿瘤厚度并不总是一个可靠的参数。虽然已经确定了一些影响黑色素瘤进展的其他临床和生物学参数，但到目前为止还没有分子标志物可以可靠地预测黑色素瘤的侵袭性。恶性黑色素瘤还表现出分子可塑性，并沿着几种细胞途径进行转分化，包括内皮细胞和神经细胞类型。黑色素瘤转分化似乎具有生物学意义和预后意义。我们研究了神经元分化对黑色素瘤肿瘤进展的影响。我们发现，神经元特异性微管相关蛋白2(MAP2)是一种主要在有丝分裂后终末分化神经元的树突中发现的蛋白，在早期侵袭性皮肤原发黑色素瘤皮损中大量表达，但在转移性皮损中表达较少或缺失。MAP2的表达似乎与肿瘤进展呈负相关。MAP2的主要功能是稳定微管。MAP2改变了微管的动态不稳定性，这是有丝分裂纺锤体形成和染色体分离的关键属性。因此，我们推测，肿瘤黑素细胞的神经元分化和MAP2基因表达的激活注定会迅速分裂，扰乱有丝分裂装置，抑制细胞增殖和肿瘤进展。对一组小样本的回顾性免疫组织化学和生存分析表明，原发肿瘤MAP2阳性的患者无病生存期显著长于MAP2阴性的黑色素瘤患者。对MAP2作用机制的研究表明，在转移性黑色素瘤细胞中过表达MAP2导致微管稳定、G2-M期停滞、生长抑制和细胞凋亡。表达MAP2的细胞显示有丝分裂纺锤体和胞质分裂缺陷，类似于微管干扰剂处理的细胞。因此，黑色素瘤早期进展中神经元分化基因的异位激活抑制了细胞分裂，并与抑制或延迟转移有关。本研究的目的是验证神经标志物在皮肤原发黑色素瘤中的表达降低了肿瘤细胞的增殖能力，增加了细胞死亡的频率，并与患者更长的无病生存有关的假设。我们建议通过研究MAP2的表达与a)黑色素瘤细胞增殖和凋亡的标记，以及b)诊断为黑色素瘤的患者的临床预后之间的关系，来测试和验证神经元标记Nestin、NEDD9和MAP2作为黑色素瘤预后标记的作用。与公共健康相关：皮肤黑色素瘤是最致命的皮肤癌。如果在癌症变得侵袭性之前及早诊断和适当治疗，黑色素瘤通常是可以治愈的。然而，目前还没有可靠的生物标志物来评估黑色素瘤的侵袭性。该项目的目标是评估新标记物在预测黑色素瘤肿瘤侵袭性方面的价值。